The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells

• Published in: Haematologica (Roma) Vol. 98; no. 11; pp. 1739 - 1747
• Main Authors: Laia Rosich, Ifigènia Saborit-Villarroya, Mónica López-Guerra, Sílvia Xargay-Torrent, Arnau Montraveta, Marta Aymerich, Neus Villamor, Elias Campo, Patricia Pérez-Galán, Gaël Roué, Dolors Colomer
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.11.2013
• Subjects: Aged; Aged, 80 and over; Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Apoptosis Regulatory Proteins - physiology; Bcl-2-Like Protein 11; Cell Movement - drug effects; Cell Movement - physiology; Coculture Techniques; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - physiology; Forkhead Box Protein O3; Forkhead Transcription Factors - physiology; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Membrane Proteins - physiology; Middle Aged; Morpholines - pharmacology; Morpholines - therapeutic use; Oncogene Protein v-akt - physiology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins - physiology; Tumor Microenvironment - drug effects; Tumor Microenvironment - physiology
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2013.088849

Phosphatidylinositol-3-kinase pathway is constitutively activated in chronic lymphocytic leukemia mainly due to microenvironment signals, including stromal cell interaction and CXCR4 and B-cell receptor activation. Because of the importance of phosphatidylinositol-3-kinase signaling in chronic lymphocytic leukemia, we investigated the activity of the NVP-BKM120, an orally available pan class I phosphatidylinositol-3-kinase inhibitor. Sensitivity to NVP-BKM120 was analyzed in chronic lymphocytic leukemia primary samples in the context of B-cell receptor and microenvironment stimulation. NVP-BKM120 promoted mitochondrial apoptosis in most primary cells independently of common prognostic markers. NVP-BKM120 activity induced the blockage of phosphatidylinositol-3-kinase signaling, decreased Akt and FoxO3a phosphorylation leading to concomitant Mcl-1 downregulation and Bim induction. Accordingly, selective knockdown of BIM rescued cells from NVP-BKM120-induced apoptosis, while the kinase inhibitor synergistically enhanced the apoptosis induced by the BH3-mimetic ABT-263. We also found NVP-BKM120 to inhibit B-cell receptor- and stroma-dependent Akt pathway activation, thus sensitizing chronic lymphocytic leukemia cells to bendamustine and fludarabine. Furthermore, NVP-BKM120 down-regulated secretion of chemokines after B-cell receptor stimulation and inhibited cell chemotaxis and actin polymerization upon CXCR4 triggering by CXCL12. Our findings establish that NVP-BKM120 effectively inhibits the phosphatidylinositol-3-kinase signaling pathway and disturbs the protective effect of the tumor microenvironment with the subsequent apoptosis induction through the Akt/FoxO3a/Bim axis. We provide here a strong rationale for undertaking clinical trials of NVP-BKM120 in chronic lymphocytic leukemia patients alone or in combination therapies.